{8 (2-Nitro-1-alkenyl)aryl{9 alkanoic (and alkenoic)-acids and related compounds

ABSTRACT

((2-Nitro-1-alkenyl)aryl)alkanoic (and alkenoic)acids and salts, esters and amide derivatives thereof, wherein the aryl ring may be further substituted by halogen, lower alkyl or hydrocarbylene substitutents. The products are diuretic and saluretic agents and are prepared by treating an ((N-substituted formimidoyl)aryl)alkanoic (or alkenoic)-acid or ester with a nitroalkane or substituted nitroalkane. When the ester of the ((2-nitro-1-alkenyl)aryl)alkanoic (or alkenoic)acid is obtained, it may be hydrolyzed to the desired ((2-nitro-1alkenyl)aryl)alkanoic (or alkenoic)acid by conventional means.

United States Patent Schultz 1 1 Jan. 14, 1975 [54] [(2-NITRO-1-ALKENYL)ARYL]ALKANOIC 2,425,320 8/1947 Hill 1. 252/149 (AND ALKENOIC)-ACIDS AND RELATED 1c mg t.

COMPOUNDS 3,352,901 11/1967 Schultz et a1. .260/515 Inventor: Everett M. Schultz, Ambler, Pa.

Assignee: Merck & Co., Inc., Rahway, NJ.

Filed: June 22, 1970 Appl. No.: 48,459

US. Cl 260/515 R, 260/141, 260/247 1, 260/247.2, 260/293.62, 260/293.72, 260/326.3, 260/465 D, 260/469, 260/471 A, 260/473 F, 260/473 A, 260/501.l5, 260/515 A, 260/515 R, 260/518 R, 260/518 A, 260/520, 260/521 R, 260/521 A, 260/558 R, 260/559 R, 260/562 P, 260/562 R, 424/309, 424/317, 424/324 Int. Cl. C07c 79/46 Field of Search 260/515 A, 515 M, 465 D, 260/471 A, 501.15

References Cited UNITED STATES PATENTS 3/1937 Salzberg et al. 167/22 Primary ExaminerJames A. Patten [57] ABSTRACT [(Z-Nitro-l-alkenyl)aryHaIkanoic (and alkenoic)acids and salts, esters and amide derivatives thereof, wherein the aryl ring may be further substituted by halogen, lower alkyl or hydrocarbylenc substitutentsv The products are diuretic and saluretic agents and are prepared by treating an [(N-substituted tormimidoyl- )aryl]alkanoic (or a1kenoie)-acid or ester with a nitroalkane or substituted nitroalkane. When the ester of the [(2-nitro-1 alkenyUaryllalkanoic (or alkenoie- )acid is obtained, it may be hydrolyzed to the desired [(2-nitro-l-alkenyl)aryllalkanoic (or a|kenoic)aeid by conventional means.

5 Claims, N0 Drawings [(Z-NITRO-l-ALKENYL)ARYL]ALKANOIC (AND ALKENOIC )-ACIDS AND RELATED COMPOUNDS This invention relates to a new class of chemical compounds which can be described generally as [(2- nitro-l-alkenyl)aryl]alkanoic (and alkenoic acids and to the nontoxic, pharmacologically acceptable salts, esters and amide derivatives thereof. It is also an object of this invention to describe a novel method of preparation for the [(2-nitro-l-alkenyl)aryl]alkanoic (and alkenoid)acid products and their corresponding salts, esters and amides.

Pharmacological studies show that the instant products are effective diuretic and saluretic agents which can be used in the treatment of conditions associated with electrolyte and fluid retention and hypertension. When administered in therapeutic dosages, in conventional vehicles, the instant products effectively reduce the amount of sodium and chloride ions in the body tissues, lower dangerous excesses of fluid levels to acceptable limits and, in general, alleviate conditions usually associated with-edema.

The [(2-nitro-l-alkenyl)aryl]alkanoic (and alkenoic)-acids (I, infra) of this invention are compounds having the following structural formula:

wherein R is alkyl, for example, lower alkyl such as methyl, ethyl, n-propyl, n-butyl, pentyl, hexyl and the metals, for example, the alkali metal and alkaline earth metal carbonates, hydroxides and lower alkoxides such as sodium carbonate, sodium hydroxide, magnesium carbonate, calcium hydroxide, potassium hydroxide, sodium methoxide and the like or from organic basis,

for example, amines such as monoalkylamines, dialklike, alkoxy alkyl, for example, lower alkoxy lower 7 1 radicals on adjacent carbon atoms of the benzene ring may be joined to form a hydrocarbylene chain (i.e., a divalent organic radical composed solely of carbon and hydrogen) containing 4 carbon atoms between their points of attachment, for example, 1,3-butadienylene and the like; Y is lower alkylene such as methylene, ethylene and the like or lower alkenylene, for example, vinylene, methyl substituted vinylene and the like; and n is an integer having a value of 1-4 and the non-toxic pharmaceutically acceptable salts thereof, for example, salts derived from the alkali metals and alkaline earth ylamines, tertiary amines or heterocyclic amines such as methylamine, dimethylamine, diethylamine, triethylamine, piperidine, pyrrolidine, morpholine and the like.

the 4-[(2-nitro-l-alkenyl)aryl]acetic acids (la, infra) having the following structural formula:

wherein R is alkyl,.for example, lower alkylsuch as methyl, ethyl and the like; X and X are hydrogen, lower alkyl such as methyl and the like orhalo such asv chloro and the like or X and X taken together, may be joined to form a l,3-butadienylene linkage; and the non-toxic, pharmaceutically acceptable salts thereof as, for example, the alkali metal and alkaline earth metal salts such as the sodium salt, potassium salt and the like. The foregoing class of compounds exhibits particularly good diuretic and saluretic activity and represents a preferred subgroup of compounds within the scope of this invention.

The [(2-nitro-l-alkenyl)aryl]alkanoic (and alkenoic- )acids (1, supra) are conveniently prepared by treating an [(N -substituted formimidoyl)aryllalkanoic (or alkenoic)acid or its corresponding ester derivative (ll, infra) with a nitroalkane or substituted nitroalkane. Al though the reaction may be conducted in the absence of a solvent, generally a solvent is employed. Suitable solvents include the lower alkanoic acids such as acetic acid, propionic acid and the like. The reaction may be conducted at a temperature in the range of from about 20 to about C; however, in practice the reaction is conveniently conducted at the reflux temperature of the particular solvent employed. The following equation illustrates this reaction:

wherein R, X, Y and n are as defined above and Rfis alkyl, for example, lower alkyl such as n-butyl, pentyl, hexyl and the like or cycloalkyl, for example, lower cycloalkyl such as cyclopentyl, cyclohexyl and the like and R is hydrogen or lower alkyl such as methyl, ethyl and the like. When an ester starting material is employed, that is, when R in formula II, supra, is lower alkyl, the resulting ester product (lb) may be hydrolyzed to the corresponding acid by conventional means as, for example, by treatment with an aqueous mixture of hydrochloric acid and acetic acid.

A preferred embodiment of this invention relates to 3 4 g The [(N-substituted formimidoyl)aryl]alkanoic (or treatment of the intermediate aldimine' (lV, infra) thus alkenoic)acids and esters (ll, supra) employed in the obtained with water. The following equation illustrates preparation of the [(Z-nitro-l-alkenyl)aryl]alkanoic this process:

n i (X) n O H v-c-o1a Reduction -v-c-o1t be chm V IV . l n i) JOR OHC 11-...

iitl

(and alkenoic)acids and esters (lb, supra).are convewherein R, X, Y and n are as defined above. niently prepared by tre'atinga (formylaryl)alkanoic (or The (formylaryl)alkanoic (and alkenoic) acids (Illa J alkenoic)-acid or ester (lll, infra) with a primary and lllb, infra) which are either nuclear unsubstituted amine, for example, with an alkylamine such as a lower or substituted with a radical other than alkyl may be alkylamine as illustrated by n-butylamine, pentylamine, prepared by treating an' appropriately substituted xyhexylamine and the like or a cycloalkylamine, for exlene (A, infra) with phosphorous pentachloride to form ample, a lower eyelealkylamihe Such as y p y the corresponding 01, a'-dichloroxylene (B, infra) folm y y in a h like- Although the r a lowed by treatment with hexamine to afford the corretion may be conducted i h a n y solvent sponding hexaminium salt which, upon treatment with which is inert or substantially inert to the reactants may an aqueous di t i i an id such s acetic be p y To insure completion of the reaction, acid and the like, affords the corresponding benwflter immiscible Solvents, Whleh form aZeOlFOPe zenedicarboxaldehyde derivative (C, infra) and the al- Wllh Water, are ge y employed; and benzene e 40 dehyde thus obtained is treated with a lower alkanoic p l he Parheularly advamegeous' The reaction 15 acid anhydride such as acetic anhydride, propionic an-- eohvemehfly conducted at the reflux temperature of hydride and the like in the presence of an alkali metal h Pameular Solvent mp y The followmg q derivative of the corresponding lower alkanoic acid Illustrates Ihls Teaetleni such as sodium acetate, sodium propionate and the like (T) n If f, n I l Y--OR R NH Y-( TOR onc R N=cH- III II wherein R R X, Y and n are as defined above. to afford the corresponding (formylaryl)alkenoic acid The (formylaryl)alkanoic (or alkenoic)acids and es- (Illa, infra) which may be employed as such as a macters (Ill, supra) employed in the preparation of the tant or may be reduced with an appropriate reducing [(N-substituted formimidoyl)aryl]alkanoic (and alagent as, for example, with a metal catalyst on a suitkenoic)acids (II, supra) are either known compounds able carrier such as 5-10 percent of a noble metal on or may be conveniently prepared b tr ti a carbon such as 5 percent rhodium on carbon and the ryl)alkanoic acid or ester (V, infra) with a reducing like, I0 yi l the rr p n ing (f myl rylmlk n i agent such as Raney ni k l ll i th presence f a acid (lllb, infra). The following equation illustrates this suitable solvent such as formic acid followed by the PFOCeSSI wherein X is hydrogen or halogen or two X radicals, on adjacent carbon atoms of the benzene ring,may be joined to form a hydrocarbylene chain; Y is lower alkenylene such as vinylene, methyl substituted vinylene and the like and Y is lower alkylene such as ethylene, methyl substituted ethylene and the like.v

The (cranoaryl)alkanoic (or alkenoic)acids (V, supra) employed in the preparation of the (formylaryl)- alkanoic (or alkenoic)acids and esters (III, supra) are conveniently prepared by either of two alternate meth- 4O ods. One method comprises treating a nuclear substituted (aminoaryl)alkanoic (or alkenoic)acid (VI, infra) with a solution of sodium nitrite and a strong acid such as hydrochloric acid, sulfuric acid, fluoboric acid and the like to form the corresponding diazonium salt 5 followed by treating said diazonium salt 'with an aque-.- ous solution of cuprous cyanide, potassium cyanide and sodium acetate The following equation illustrates this process:

CuCN/KCN wherein X, Y and n are as defined above and X is halo, sulfo, fluoboro and the like.

A second method for preparing the (cyanoaryl)- alkanoic (or alkenoic)acids and esters (Vb) and one which is limited to the (cyanoaryl)alkanoic (or alkenoic)acids and esters wherein X" in formula Vb is hydrogen or lower alkyl or two X" radicals, on adjacent carbon atoms of the benzene ring may be joined 7 8 l;n)n ("D icwn (F y-c-orz CuCN Y-C-OR X" s NC--....

VII Vb wherein R Y and n are as defined above; X" is hydrowherein X and n are defined above. gen or lower alkyl or two X" radicals, on adjacent car- Included within the scope of this invention are the hon atoms, may be joined to form a hydrocarbylene 10 non-toxic, pharmacological acceptable salts of the inchain and X is halo such as bromo and the like. stant products. In general, any base which will form a The nuclear amino substituted arylacetic acids (Via, salt with the foregoing [Z-nitro-l-alkenyl)aryl]alkanoic infra) employed as starting materials in the preparation (and alkenoic)-acids and whose pharmacological properties will not cause an adverse physiological effect when ingested by the body system is considered as of the (cyanoaryl)alkanoic (and alkenoic)acid derivatives (V, supra) are conveniently prepared by the hydrolysis of an (acetamidophenyl)thioacetomorpholide being within the scope of this invention. Suitable bases (VIII, infra) with an aqueous solution of an inorganic thus include, for example, those derived from the alkali acid such as hydrochloric acid and the like. The followmetals and alkaline earth metals, for example, the aling equation illustrates this process: kali metal and alkaline earth metal carbonates, hydroxwherein X and n are as defined above. 0 ides and alkoxides such as sodium carbonate, sodium The (acetamidophenyl)thioacetomorpholides (VIII, hydroxide, magnesium Carbonate, Calcium hydroxide supra) employed in the preparation of th cl potassium hydroxide, sodium ethoxide and the like, amino substituted phenylacetic acids (VIa, supra) are mmonia, primary, secondary and tertiary amines, for prepared by treating an acetamidoacetophenone (IX, amp e, mo oo e a kylamines such as methylinfra) with sulfur and morpholine at temperatures in amine. hyl min n the e. di- O er alkylamines the range of from about 100 to 130C. for a period f such as dimethylamine, diethylamine and the like, trifrom 1 to 10 hours. The following equation illustrates lower alkylamines such as triethylamine and the like. this process: alicyclic amines such as cyclopentylamine and the like (X) n (X) n s O 0 li II \CCH Sulfur/Morpholine CH C.I\ CH3CNH a CH cm a IX VIII wherein X and n are as defined above. or heterocyclic amines such as piperidine, pyrrolidine,

The acetamidoacetophenones (IX, supra) employed morpholine and h i in the preparation of the (acetamidophenyl)thi- Also included within the scope of this invention are t h fid (V111 Supra) are i h known the ester and amide derivatives of the instant products compounds or may be prepared by t ati g an approwhich are prepared by conventional methods known to priately substituted acetanilide (X, infra) with an acetyl those kil i h Th f r e mp if h r ester halide su h as t l hl id d h lik i h presderivatives besides those disclosed are desired, they ence of aluminum chloride. The reaction may be conmay be prepared by the reaction of a [(2-nitro-lducted without a solvent; however, in general, solvents alkenyl)ary l (oralkcfloichcid Of this invenwhich are inert or substantially inert are employed such tion with an alcohol as, for example, with a lower alkaas dichloromethane, benzene, nitrobenzene, carbon dinol such as methanol, ethanol, n-propanol and the like. sulfide and the like. The following equation illustrates The amide derivatives of the [(2-nitro-lthis reaction: alkenyl)aryl]alkanoic (and alkenoic) acids of this in- (X) n o (X) n o 0 o cn cc1 ll ccn cn cnn CH 3CNH ALC13 vention may be prepared by converting a [(2-nitro-1- alkenyl)aryl]alkanoic (or alkenoic)acid to its corresponding acid chloride by treating said acid with thionyl chloride followed by treating the acid chloride formed with ammonia or an appropriate mono-lower alkylamine or di-lower alkylamine to produce the corresponding amide compound or by treating the esters heretofore described with ammonia or an amine. These and other equivalent methods for the preparation of the ester and amide derivatives of the instant products will be apparent to one having ordinary skill in the art and to the extent that said derivatives are both nontoxic and physiologically acceptable to the body systern, said derivatives are the functional equivalent of the corresponding [(2-nitro-l-alkenyl)aryl]alkanoic (and a1kenoic)acids.

The examples which follow illustrate the [(2-nitro-lalkenyl)aryl]alkanoic (and alkenoic)acids of this invention and the method by which they are prepared. However, the examples are illustrative only and it will be apparent to those having ordinary skill in the art that all of the products embraced by formula l, supra, may also be prepared in an analogous manner by substituting the appropriate starting materials for those set forth in the examples.

EXAMPLE 1 [4-(2-Nitro-1-Propenyl)phenyl]acetic Acid A mixture of ethyl (4-formylphenyl)acetate (3.8 g., 0.02 mole), benzene (30 m1.) and n-butylamine (1.46 g., 0.02 mole) is refluxed under a constant water separator until evolution of water is complete (about 2 hours). The benzene then is evaporated under reduced pressure to afford ethyl [4-(N-n-butylformimidoyl)- phenyllacetate. The pale yellow ethyl [4-(N-nbutylformimidoyl)pheny1]acetate is dissolved in acetic acid (20 ml.) and nitroethane (5.4 g., 0.07 mole) is added. The mixture is heated to boiling and then allowed to cool. The yellow-green solution then is poured into ice water (125 ml.). The green oil that separates is extracted with ether. The ether extract is washed with water, dried over sodium sulfate, filtered and the ether evaporated. The residual oil, crude ethyl [4-(2- nitro-l-propenyl)phenyl]-acetate, is dissolved in a mixture of acetic acid (30 ml.), water (20 ml.) and concentrated hydrochloric acid (1.0 ml.). The mixture is refluxed for 1 hour and then kept at 20- 25C. for 2 days. The pale green crystals that separate are collected on a filter and crystallized from an ethanol-water solution (1:1) to obtain 1.6 g. of [4-(2-nitro-lpropenyl)-phenyl]acetic acid, m.p. 149-152C.

Elemental analysis for C H NO Calc.: C, 59.72; H, 5.02; N, 6.33;

Found: C, 59.70; H, 4.92; N, 6.48.

EXAMPLE 2 [3-Chloro-4-(2-Nitro-1-Propenyl)phenyl]acetic Acid Step A: (3-Chloro-4-Acetamidophenyl)thioacetomorpholide An intimate mixture of 3ch1oro-4- acetamidoacetophenone (30 g., 0.143 mole), precipitated sulfur (4.6 g., 0.143 mole) and morpholine (13.5 g., 0.158 mole) is heated gradually until a melt forms (at about 100C.). The mixture then is heated up to 120-130C. and kept at this temperature for 7 hours. The hot mixture then is poured into water (250 ml.) On gentle warming, the resulting syrup solidifies to a dark yellow mass, which is pulverized in a mortar, collected on a filter and washed with water. After crystallization from 59 percent alcohol, there is obtained 31.3 g. (72 percent yield) of (3-ehloro4acetamidophenyl)thioacetomorpholide, m.p. l25126.5C.

Elemental analysis for C H CLN O S:

Calc.: C, 53.75; H, 5.48; S, 10.25;

Found: C, 53.40; H, 5.35; S, 10.29.

Step B: (3-Chloro-4-Aminophenyl)acetic Acid The (3-chloro-4-acetamidophenyl )thioacetomorpholide (93.8 g., 0.3 mole) is added to 6N hydrochloric acid (500 ml.) and the mixture is refluxed for 1 /2 hours. The mixture then is cooled to 60C. and filtered. The filtrate is evaporated to dryness under reduced pressure at about C. and the residue is taken up in water (1 1.). The solution is brought to pH 6 by the ad' dition of a 20 percent sodium hydroxide solution and then to pH 8 with a 10 percent sodium bicarbonate solution. The solution is stirred with decolorizing charcoal for 1 hour, warmed to 80C. and filtered through a pad of diatomaceous earth. The warm solution is acidified with acetic acid and cooled to about 10C. The pale yellow solid that separates is collected and is crystallized from water to obtain 43.6 g. (78 percent yield) of (3-chloro-4-aminophenyl)acetic acid. m.p. 136137C.

Elemental analysis for C H CLNO Calc.: C, 51.76; H, 4.34; N, 7.55;

Found: C, 52.14; H, 4.25; N, 7.74.

Step C: (3-Chloro-4-Cyanophenyl)acetic Acid Concentrated hydrochloric acid (50 ml.) is added dropwise over a period of 15 minutes to a solution of sodium nitrite (21 g.) in water ml.) at 0C. with stirring. A solution of (3-chloro-4-aminophenyl)acetic acid (37.0 g., 0.2 mole) in a mixturc'of concentrated hydrochloric acid (20 ml.) and water (200 ml.) is cooled to 10C. and is added slowly, with stirring, to the solution of nitrous acid prepared above maintaining the temperature of the reaction mixture at 05C. by external cooling. Concurrently, additional solid sodium nitrite (10 g.) (total 31 g., 0.45 mole) is added in small portions to the reaction mixture. The mixture then is stirred at 05C. for 20 minutes and the excess nitrous acid is destroyed by the addition of a solution of urea (15 g., 0.25 mole) in water (50 ml.). Caution: The remainder of this preparation must be run in a good hood as hydrogen cyanide gas is evolved. The cold dark redblack diazonium solution then is added portionwise to a well-stirred cold (10C.) solution of cuprous cyanide (20 g., 0.22 mole), potassium cyanide (46 g., 0.70 mole) and sodium acetate trihydrate (400 g., 3.0 mole) in water (650 ml.). The black mixture is stirred at 25C. for 1 hour, at 50C. for 1 hour and then kept at 2025C. for 16-20 hours. The mixture then is heated to 60C. and filtered by gravity to remove some tarry material. the filtrate is acidified to Congo Red with concentrated hydrochloric acid. A tan solid, which precipitates, is removed by suction filtration and discarded. The filtrate is cooled and extracted several times with ether. The combined ether extracts are washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and the ether evaporated under reduced pressure. The yellow brown residual oil solidifies slowly to a dark solid (30 g., m.p. 103-112C.). The crude product is dissolved in ether (800 ml.), treated with decolorizing charcoal and the solution evaporated to ml. Ligroin (about 150 ml.)

is added in small portions to incipient precipitation and the mixture is cooled to C. for 16 hours. This type of recrystallization is repeated to obtain 15.2 g. (39 percent yield) of (3-chloro-4-cyanophenyl)acetic acid, m.p. 1131l5C.

Elemental analysis for C H CLNO Calc.: C, 55.26; H, 3.09; N, 716; C1, 18.13;

Found: C, 55.36; H, 2.98; N, 7.21; Cl, 18.14.

Step D: (3-Chloro-4-Formylphenyl)acetic Acid (3-Chloro-4-cyanophenyl)acetic acid (15.6 g., 0.08 mole) is dissolved in 65 percent aqueous formic acid (150 ml.) and Raney nickel alloy (20 g.) is added. The mixture is stirred and refluxed for 1% hours. The reaction mixture is then cooled to 60C. and additional Raney alloy (28 g.) is added slowly (foaming). The reaction mixture is again stirred and refluxed for 1% hours. The reaction mixture is cooled, filtered through diatomaceous earth (suction) and the residue is washed on the filter with hot water (300 ml.). The aqueous filtrate is reserved and the residue in the filter funnel is then extracted with hot ethanol (400 ml.) for minutes. The extract is filtered as above and the residue washed with 300 ml. of hot alcohol. The combined alcoholic extracts are filtered and concentrated to 50 ml. under reduced pressure. The concentrated alcoholic solution is then added to the original aqueous filtrate and the whole is concentrated at reduced pressure to 100-150 ml. The residue is diluted with water (1 l.) and the aqueous mixture is extracted with chloroform (4 X 200 ml.). The chloroform extract is washed with a saturated sodium chloride solution and dried over sodium sulfate. The chloroform is removed by evaporation to afford a pale yellow residue which is recrystallized from benzene (charcoal) to yield 8.1 g. of (3-chloro-4- formylphenyl)acetic acid, m.p. l07l09C. This product is satisfactory for the next step. A sample may be further crystallized from ether-cyclohexane (7:5) to obtain substantially pure (3-chloro-4-formylphenyl)acetic aicd, m.p. 1101l2C.

Elemental analysis for C H CLO Calc.: C, 54.43; H, 3.55; Cl, 17.85;

Found: C, 54.51; H, 3.63; Cl, 17.75.

Step E: [3-Chloro-4-(2-Nitro-l-propenyl)phenyl]acetic Acid A mixture of (3-chloro-4-formylphenyl)acetic acid (1.0 g., 0.005 mole), n-butylamine (0.8 g., 0.011 mole) and benzene ml.) is heated at reflux under a constant water separator for 1 /2 hours (A small quantity of water is thus removed from the reaction mixture). the yellow solution is concentrated to dryness under vacuum to afford [4-(N-n-butylformimidoyl)-3-chlorophenyl]acetic acid as a gum. The [4-(N-nbutylformimidoyl)-3-chlorophenyl]acetic acid is dissolved in nitroethane (1.4 g., 0.019 mole) and acetic acid (5 ml.) and is heated at reflux for several minutes, the solution is poured into water and ice and the mixture is acidified with concentration hydrochloric acid and cooled. The crude product is collected and is recrystallized from benzene-cyclohexane to afford 0.3 g. (23 percent yield) of [3-chloro-4-(2-nitro-l-propenyl)- phenyl]acetic acid, m.p. l31135C.

Elemental analysis for C H CLNO Calc.: C, 51.68; H, 3.94; N, 5.50;

Found: C, 51.96; H, 3.82; N, 5.34.

EXAMPLE 3 [4-(2-Nitro-l-Propenyl)-2-Methylphenyl]acetic Acid Step A: (4-Acetamido-2-Methylphenyl)acetothi omorphilide 4-Acetyl-3-methylacetanilide (64.5 g., 0.337 mole) and flowers of sulfur (11.9 g., 0.372 mole) is mixed in a 300 ml. flask. Morpholine (32.4 g., 0.372 mole) is added and the flask is placed in an oil-bath at C. An air condenser is added and the bath temperature brought to C. and held at l25l30C. for 7 hours. The dark brown liquid is then poured with vigorous stirring into warm water (1 1.). The product oils-out at first but then solidifies into a tan powder after a few minutes. The crude product is crystallized from ethanol to afford 51.0 g. of (4-acetamido-2- methylphenyl)acetothiomorphilide, m.p. l74l76C.

Elemental analysis for C H N O S:

Calc.: C, 61.61; H, 6.89; N, 9.58;

Found: C, 61.31; H, 6.83; N, 9.49.

Step B: (4-Amino-2-Methylphenyl)acetic Acid A 2 l. round-bottomed flask is charged with (4- acetamido-Z-methylphenyl)acetothiomorphilide (87.5 g., 0.3 mole), concentrated hydrochloric acid (250 ml.) and water (500 ml.). The mixture is stirred magnetically on a steam bath. The reaction mixture becomes clear after about /zhour and the heating and stir ring are continued for 3 hours. The clear solution is evaporated under reduced pressure and the residual solid is dissolved in hot water (500 ml.) and is filtered. The clear yellow filtrate is made weakly alkaline (pH of 8) with a 20 percent sodium hydroxide solution ml.) and then is acidified with glacial acetic acid (25 ml.) to a pH of 5 and set aside to crystallize. Filtration yields 39.6 g. of (4-amino-2-methylphenyl)acetic acid, m.p. 187190C. as a beige powder. Several recrystallizations from ethanolwater afford substantially pure product, m.p. 192-194C.

Elemental analysis for C H NO Calc.: C, 65.45; H, 6.71; N, 8.48;

Found: C, 66.07; H, 6.76; N, 8.54.

Step C: (4-Cyano-2-Methylphenyl)acetic Acid A solution of sodium nitrite (20.8 g., 0.30 mole) in water (80 ml.) is added dropwise to a well stirred suspension of (4-amino-2-methylphenyl)acetic acid (33.0

g., 0.20 mole) in water (200 ml.) and concentrated hydrochloric acid (80 ml.) at 0C. After the addition, the clear diazonium solution is stirred at 0C. for 1 hour and then the excess nitrous acid is destroyed by the dropwise addition of urea (10 g.) in water (25 ml.). The clear tan solution (turned dark red on standing) is added portionwise to a well stirred solution of cuprous cyanide (20.0 g., 0.204 mole), potassium cyanide (46.0 g., 0.732 mole), and sodium acetate trihydrate (334 g., 2.46 mole) in water (500 ml.) at 0C. The deep purple solution is stirred at room temperature for one hour, at 50C. for 1 hour, and then overnight at room temperature. The reaction mixture is filtered and the filtrate is acidified with concentrated hydrochloric acid (250 ml.). After cooling to I about 5C. the (4-cyano-2-methylphenyl)acetic acid is obtained as a tan powder, 30.75 g., m.p. l60170C,. Recrystallization from an ethanol-water mixture yields 16.4 g. of (4-cyano-2-methylphenyl)acetic acid, m.p. 176.5C. Another recrystallization from ethanolwater mixture affords the analytical sample with a m.p. of 176.5177C.

Elemental analysis for C H NO Calc.: C, 68.56; H, 5.18; N, 8.00;

Found: C, 68.68; H, 5.20; N, 8.06.

Step D: (4-Formyl-2-Methylphenyl)acetic Acid Raney nickel alloy (30 g.), (4-cyano-2- methylphenyl)-acetic acid (29.2 g., 0.165 mole), and 75 percent aqueous formic acid (450 ml.) are refluxed with vigorous stirring for one hour. The mixture is cooled, filtered by suction, and the residue is washed with warm ethanol (3 X 100 ml.). The filtrate and washings are combined and evaporated under reduced pressure to about 300 ml. The concentrate is cooled, diluted with water (1 l.) and is extracted with several portions of chloroform (4 X 200 ml.). The chloroform extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure. The crude product is crystallized from water to afford 16.3 g. of (4-formyl-2-methylphenyl)-acetic acid, m.p. 117-118.5C.

Elemental analysis for C H O Calc.: C, 67.40; H, 5.66;

Found: C, 67.47; H, 5.80.

Step E: [4-(2-Nitro-1-Propenyl)-2-Methylphenyl]acetic Acid (4-Formyl-2-methylphenyl)acetic acid (7.1 g., 0.04 mole), n-butylamine (8.0 ml., 0.08 mole), and benzene (150 ml.) are refluxed under a water separator for 2 hours. The benzene is evaporated under reduced pressure to afford 4-(N-n-butylformimidoyl)phenylacetic acid as a pale yellow powder. The 4-(N-n-butylformimidoyl)phenylacetic acid is dissolved in a solution of nitroethane (36 ml., 0.50 mole) and acetic acid (50 ml.) and is heated at reflux for several minutes. The resulting green solution is cooled and poured into cold water (600 ml.) and stirred vigorously at room temperature for 5 hours. After cooling overnight, in a refrigerator, the product is collected as a light green powder, 8.0 g., m.p. 153-156C. Recrystallization from acetic acid-water yields 6.5 g. of substantially pure [4-(2- nitro-1-propenyl)-2-methylphenyl]acetic acid as pale green thin plates, m.p. l57158C.

Elemental analysis for C H NO.,:

Calc.: C, 61.27; H, 5.57; N, 5.96;

Found: C, 60.85; H, 5.51; N, 6.27.

EXAMPLE 4 4-(2-Nitro-1-Propenyl)cinnamic Acid 4-Formylcinnamic acid (3.5 g., 0.02 mole), nbutylamine (4 ml., 0.040 mole), and benzene (100 ml.) are refluxed under a water separator for one hour. The benzene is evaporated under reduced pressure to afford 4-(N-n-butylformimidoyl)-cinnamic acid as an oil which is heated to gentle reflux with nitroethane (8 ml., 0.111 mole) and acetic acid (20 ml.). The resulting tan solution is allowed to cool to room temperature to afford the crude product 3.2 g., m.p. 232-234C. as small yellow needles. Recrystallization from acetic acid affords 2.95 g. of substantially pure 4-(2-nitro-1- propenyl)-cinnamic acid, m.p. 232232.5C.

Elemental analysis for c zHnNoq:

Calc.: C, 61.80; H, 4.75; N, 6.01;

Found: C, 62.11; H, 4.55; N, 6.13.

EXAMPLE 5 [3-(2-Nitro-1-Propeny1)phenyl]acetic Acid Step A: (3-Formylphenyl)acetic Acid A mixture of 3-cyanophenylaeetic acid (10.5 g., 0.065 mole), Raney Alloy (11.0 g.), and 65 percent aqueous formic acid (200 ml.) are heated at reflux for 45 minutes with stirring. After cooling, an additional 10 g. of Taney Alloy is added and the reaction mixture is again heated at reflux for 1 hour. The reaction mixture is filtered and the insoluble residue is triturated with warm ethanol and filtered again.

The filtrates are concentrated to near dryness under vacuum and the residue taken up in water; the aqueous mixtures are combined and extracted with several portions of chloroform. After drying over sodium sulfate, the chloroform solution is concentrated to dryness under vacuum to afford 3-formylphenylacetic acid, a pale yellow solid. The product is recrystallized from benzene to afford 6.5 g. (61% yield) of (3-formylphenyl)acetic acid, m.p. 9799C.

Elemental analysis for C H O Calc.: C, 65.85; H, 4.91;

Found: C, 65.43; H, 4.78.

Step B: [3-(2-Nitro-l-Propenyl)phenyl]acetic Acid A mixture of 3-formylphenylacetic acid (1.64 g., 0.01 mole), n-butylamine (1.55 g., 0.021 mole) and benzene (25 ml.) is heated at reflux under a constant water separator for 1 /2 hours; a small quantity of water (0.1 ml.) is thus removed from the reaction mixture. The yellow solution is concentrated to dryness under vacuum to afford [3-(N-n-butylformimidoyl)phenyllacetic acid as an oily residue which is taken up in nitroethane (2.7 g., 0.036 mole), acetic acid (10 ml) and heated to reflux for several minutes. The solution is poured into water and ice and the reaction mixture is acidified with concentrated hydrochloric acid and cooled. The crude product is collected and recrystallized from benzene-cyclohexane to afford 1.05 g. (48 percent yield) of ['3-(2-nitro-l-propenyl)phenyl]- acetic acid, m.p. 72C.

Elemental analysis for C H NO,:

Calc.: C, 59.72; H, 5.02; N, 6.33;

Found: C, 59.66; H, 4.49; N, 6.38.

EXAMPLE 6 [4-(2-Nitro-1-propenyl)-1-Naphthyl]acetic Acid Step A: Ethyl (4-Bromo-l-Naphthyl)acetate (4-Bromo-1-napthyl)acetic acid 101 g., 0.382 mole) is dissolved by warming and stirring in thionyl chloride (1.0 l.) and the resulting yellow solution is refluxed for 2 hours. The excess thionyl chloride is removed under reduced pressure. The residual brown liquid is washed twice with anhydrous benzene (2 X 200 ml.) and evaporated to dryness each time to remove the last traces of thionyl chloride. To the residual brown oil is added absolute ethanol (1.01 1.) containing pyridine (31.7 g., 0.40 mole). After the initial exothermic reaction, the solution is heated under reflux for 45 minutes and the ethanol is evaporated at reduced pressure. The light brown solid is dissolved in ether (500 ml), washed successively with water, two portions of saturated sodium bicarbonate [to remove any 4-formyl-l-naphthyl)acetic acid formed] and water. The ether solution is dried over magnesium sulfate, filtered and the ether is evaporated. The residual oil solidifies into a tan crystalline mass of needles, 108 g., m.p. 4345.5C. The crude product is distilled under vacuum to yield ethyl (4-bromo-1-naphthyl)acetate as a light yellow liquid, 103.5 g., b.p. l35C./0.050.07 mm. which crystallizes immediately upon cooling, m.p. 4446C.

Elemental analysis for C H BrO z Calc.: C, 57.36; H, 4.47;

Found: C, 57.13; H, 4.38.

Step B: Ethyl (4-Cyano-1-Naphthyl)aeetate In a l l. flask fitted with a condenser and a stirrer is placed ethyl (4bromo-l-naphthyl)acetate (103 g., 0.352 mole), cuprous cyanide (35 g., 0.375 mole), dimethylformamide (600 ml.), and pyridine (5 ml.). The

mixture is heated under reflux with vigorous stirring for 6 hours. This hot solution is poured, with stirring, into an ammonium hydroxide solution (2 1., 15N) containing crushed ice (1.5 dg.). The resulting blue liquid and red-brown solid is extracted with chloroform (8 X 500 ml), the extract is washed with dilute hydrochloric acid, water, and dried over magnesium sulfate. The chloroform is evaporated under reduced pressure and the dark residual oil is distilled under vacuum to afford ethyl (4-cyano-1-naphthyl)-acetate as a reddish-orange oil, 75.4 g., b.pv 165173C./0.030.05 mm. which solidifies upon standing, m.p. 5559C. This solid is recrystallized from cyclohexane-chloroform to afford 61 g. of ethyl (4-cyano-l-naphthyl)acetate, m.p.

61.5-63.0C. An analytical sample is prepared by re crystallization from cyclohexane-petroleum ether to obtain a pure sample, m.p. 63.564.5C.

Elemental analyis for C H NO Calc.: C, 75.30; H, 5.48; N, 5.85; Found: C, 75.51; H, 5.42; N, 5.80. Step C: ethyl (4-Formyl-1-naphthyl)acetate Raney nickel alloy (61 g.), ethyl (4-cyano-lnaphthyl)-acetate (61 g., 0.255 mole), and 75 percent aqueous formic acid (1 1.) are refluxed with vigorous stirring for 1 /2 hours in a 51; flask. The reaction mixture is then cooled slightly and an additional charge of alloy (122 g.) is added with water (350 ml.). The heating and stirring are continued for an additional 2 hours. Much foaming occurs but because of the size of the flask offers no problem. The reaction mixture then is cooled, filtered, and the flask and residue are washed with several portions of warm ethanol (2 X 400 ml.). The washings and the original filtrate are combined and evaporated under reduced pressure to about 1 l. The greenish brown solution is poured into 4 1. water and extracted with chloroform (8 X 250 ml.). The beige extracts are combined and washed with a saturated sodium bicarbonate solution (2 X 500 ml.) and then dried over magnesium sulfate. The chloroform is evaporated under reduced pressure to yield the crude ethyl (4-formyl-l-naphthyl)acetate, 34.7 g., as a brown oil. Distillation affords substantially pure ethyl (4-formyl-l-naphthyl)acetate as a faint yellow oil, 27.7 g., b.p. 157l64C./0.- 09-010 mm. Elemental analysis for C H O Calc.: C, 74.36; H, 5.83; Found: C, 73.52; H, 5.81. Step D: [4-(2-Nitro-l-Propenyl)1-Naphthyl]acetic Acid Ethyl (4-formyl-l-naphthyl)acetate (5.24 g., 0.0218 mole), n-butylamine (2.16 ml., 0.0218 mole), and benzene (80 ml.) are refluxed under a water separator for 2 /2 hours. The benzene is evaporated under reduced pressure to afford ethyl [4-(N-n-butylformimidoyl)-1- naphthyllacetate as a yellow oil. The ethyl [4-(N-nbutylformimido)-1-naphthyl]acetate is dissolved in a solution of acetic acid (40 ml) and nitroethane (14.5 ml., 0.201 mole). The resulting yellow solution is heated to gentle reflux and then the solution is evaporated under reduced pressure. The oily orange residue is dissolved in acetic acid (100 ml.). Water (40 ml.) containing concentrated hydrochloric acid (4 ml.) is then added and the solution is refluxed for 1% hours. The resulting light brown solution is poured, with stirring, into cold water (500 ml.) and the product separates as a light yellow powder, 4.25 g., m.p. -180C. This crude product is recrystallized seven times from ethanol Water to yield 0.56 g. of substantially pure [4-(2-nitro-1-propenyl)-1-napthyl]acetic acid as tiny yellow needles, m.p. l9ll93C.

Elemental analysis for C, H, NO

Calc.: C, 66.41; H, 4.83;

Found: C, 66.05; H, 5.16.

EXAMPLE 7 [4-(2-Nitro-l-Propenyl)-l-Naphthy11acetic Acid Step A: (4-Formyl-l-Naphthy1)acetic Acid The sodium bicarbonate extracts from Example 6, Step A, are combined and acidified with dilute hydrochloric acid to afford 10.7 g. of crude 4-formyl-lnaphthylacetic acid as a light beige powder, m.p. l80-184C. Several recrystallizations from an ethanolwater mixture yield substantially pure (4-formyl-1-naphthyl)acetic acid, m.p. l92.5-193.5C.

Elemental analysis for C H O- Calc.: C, 72.89; H, 4.71;

Found: C, 73.08; H, 4.66.

Step B: [4-(2-Nitro-1-Propenyl)-1-Naphthyllacetie Acid (4-Formyl-l-naphthyl)acetic acid (2.14 g., 0.01 mole), n-butylamine (2.0 ml., 0.02 mole), and benzene (50 ml.) are refluxed under a water separator for 3 hours. The benzene is evaporated under reduced pressure to afford [4-(N-n-butylformimidoyl)-l-naphthyl- ]acetic acid as an orange oil. The [4-(N-nbutylformimidoyl)-l naphthyllacetic acid is dissolved in a solution of nitroethane (9 ml., 0.125 mole) and acetic acid (25 ml.) and heated to reflux for several minutes. The resultant clear orange liquid is cooled and poured, with stirring, into cold water (300 ml.). The product separates as a gum which solidifies on standing at 5C. overnight. This crude product (2.4 g.) is recrystallized 10 times from an ethanol water mixture to yield 0.17 g. of substantially pure [4-(2-nitro-1-propenyl)-lnaphthyl]acetic acid as a yellow powder, m.p. l92-193.5C.

Elemental analysis for C, H NO Calc.: C, 66.41; H, 4.83;

Found: C, 66.13; H, 4.91.

EXAMPLE 8 {3-[2,3-Dichloro-4-(2-Nitro-l-Propenyl)phenyll}propionic Acid Step A: 01,01'-2,3-Tetrachloro-p-Xylene To 2,3-dichloro-p-xylene g., 1 mole) is added, gradually, phosphorous pentachloride (408 g., 2 mole) with stirring. With continued stirring, the mixture is heated to -200C. until hydrogen chloride gas ceases to be evolved. The mixture then is allowed to cool. The mixture is added carefully to water and the organic material is taken up in chloroform. The chloroform extract is washed with water,

10 percent sodium bicarbonate and with water, dried over sodium sulfate and the chloroform is evaporated to afford a,a'-2,3-tetrachloro-p-xylene which is used directly in the next step.

Step B: 2,3-Dichloroterephthalic Aldehyde Hexamine (62 g., 0.44 mole) is dissolved in warm chloroform (500 ml.) with stirring. Then a,a-2,3 tetrachloro-p-xylene (48.8 g., 0.2 mole) in a minimum amount of warm chloroform is added. the mixture is refluxed for 4 hours and then allowed to cool. The hexaminium salt that separates is collected and washed with chloroform. The hexaminium salt (52.4 g., 0.1 mole) is added to 50 percent acetic acid (180 ml.) and the mixture is refluxed for about 2 hours. The mixture is acidified to Congo Red and refluxed for an additional minutes. The mixture is cooled and diluted with water until the separation of the 2,3-dichloroterephthalic aldehyde is complete. The 2,3-dichloroterephthalic aldehyde is collected and purified by crystallization from a suitable solvent such as alcohol or alcohol-water.

Step C: 2,3-dichloro-4-Formylcinnamic Acid A mixture of 20.3 g. (0.1 mole) of 2,3- dichloroterephthalic aldehyde, acetic anhydride (10.2 g., 0.1 mole) and anhydrous sodium acetate g.) are combined and heated at 180C. under a short air condenser for 8 hours. The cooled mixture is diluted with water and extracted with ether. The ether solution is extracted thoroughly with dilute sodium bicarbonate solution. The aqueous extract is washed with ether and acidified with dilute hydrochloric acid. 2,3-dichloro-4-formylcinnamic acid that separates is collected, dried and recrystallized from benzene or alcohol.

Step D: 3-(2,3-Dichloro-4-Formylphenyl)Propionie Acid 2,3-Dichloro-4-formylcinnamie acid (10 g.) is dissolved in ethanol and 250 mg. of rhodium on carbon catalyst (5 percent) is added. The mixture is hydrogenated at 30 p.s.i. original pressure. The hydrogenation is interrupted when exactly 1 mole of hydrogen has been absorbed. The catalyst is removed and the alcohol is evaporated. The residue is crystallized from benzene to obtain 3-(2,3-dichloro-4-formylphenyl)propionie acid.

Step E: {3-[2,3-dichloro-4-(2-Nitro-l- Propenyl)phenyl]) Propionic Acid By substituting for the (3-ehloro-4-formylphenyl)acetic acid of Example 2, Step E, an equimolar quantity of 3-(2,3-diehloro-4-formylphenyl)propionic acid and by following substantially the procedure described therein, there is obtained. {3-[2,3-dichloro-4-(2-nitrol-propenyl)phenyl]} propionic acid.

EXAMPLE 9 3-[2,3-Dichloro-4-(2-nitro-l-Propenyl)Phenyl]-2- Methylacrylic Acid Step A: 3-(2,3-Dichloro-4-Formylphenyl)-2- Methylacrylic Acid By substituting for the acetic anhydride and sodium acetate of Example 8, Step C, an equimolar quantity of propionic anhydride and sodium propionate and by following substantially the procedure described therein, there is obtained 3-(2,3-diehloro-4-formylphenyl)-2- methylacrylic acid.

Step B: 3-[2,3-Diehloro-4-(2-nitro-l- Propenyl)Phenyl]-2-Methylacrylic Acid By substituting for the (3-chloro-4-formylphenyl)acetic acid of Example 2, Step E, an equimolar quantity of 3-(2,3-dichloro-4-formylphenyl)-2-methylacrylic acid and by following substantially the procedure described therein, there is obtained 3-[2,3-dichloro-4-(2- nitro-l-propenyl)phenyl]-2-methylacrylic acid.

EXAMPLE l0 [2,3-Dichloro-4-(2-Nitro-l-Propenyl)]Cinnamic Acid By substituting for the (3-chloro-4-formylphenyl)acetic acid of Example 2, Step E, an equimolar quantity The.

of 2,3-dichloro-4-formyleinnamic acid and by following substantially the procedure described therein, there is obtained [2,3-dichloro-4-( 2-nitrol propenyl)]cinnamic acid.

EXAMPLE ll 4-(2-Nitro-l-Propenyl)hydrocinnamic Acid Step A: 4-Cyanohydroeinnamic Acid A solution of sodium nitrite (20.8 g., 0.30 mole) in water ml.) is added dropwise to a well-stirred solution of 4-aminohydrocinnamic acid (34.0 g., 0.206 mole) in water (200 ml.) and concentrated hydrochloric acid (80 ml.) at 0C. After the addition, the clear diazonium solution is stirred at 0C. for 1 hour and then the excess nitrous acid is destroyed by the dropwise addition of urea (10 g.) in water (25 ml.). The clear tan solution is added portionwise to a well stirred solution of cuprous cyanide (20.0 g., 0.204 mole), potassium cyanide (46.0 g., 0.732 mole), and sodium acetate trihydrate (334 g., 2.46 mole) in water (500 ml.) at 0C. The dark solution is stirred at room temperature for 1 hour at 50C. for l hour, and then overnight at room temperature. The mixture is then warmed to 60C. and filtered by gravity. The filtrate is treated with concentrated hydrochloric acid (250 ml.) to yield the crude productas a tan solid. This tan solid is extracted in a Soxhlet with ether. Evaporation of the ether yields 22.2 g. of product, m.p. l35-l39C. Recrystallization from water yields the substantially pure 4-cyanohydroeinnamie acid as yellow needles, 18.5 g., m.p. l38l 39C.

Step B: 4Formylhydrocinnamic Acid Raney nickel alloy (20 g.), 4-eyanohydrocinnamic acid (18.5 g., 0.106 mole), and 75 percent aqueous formic acid (300 ml.) are refluxed with vigorous stirring for 1 hour. The mixture is cooled, filtered by suction, and the residue washed with three ml. portions of warm ethanol. The filtrate and washings are combined and evaporated under reduced pressure to about 300 ml. The concentrate is cooled, diluted with water l l. and extracted with four 200 ml. portions of chloroform. The extracts are combined, dried over magnesium sulfate and evaporated under reduced pressure to yield the crude product as off white needles, 13.3 g., m.p. l36138C. An analytical sample, m.p. l35.5-l36.5C, is prepared by recrystallization from benzene.

Elemental analysis for CwHmOjgl Calc.: C, 67.40; H, 5.66;

Found: C, 67.42; H, 5.36.

Step C: 4-(2-Nitro-l-Propenyl)hydroeinnamic Acid 4-Formylhydrocinnamic acid (5.33 g., 0.03 mole), n-butylamine (6 ml., 0.06 mole), and benzene (I25 ml.) are refluxed under a water separator for 1 /2 hours. The benzene is evaporated under reduced pressure to afford 4-(N-n-butylformimidoyl )hydrocinnamic acid as a yellow oil which is heated to gentle reflux with nitroethane (10.8 ml., 0.15 mole) and acetic acid (40 ml.). The resulting dark green solution is cooled and poured with stirring into cold water (400 ml.). The crude product obtained as a light green powder, 66 g., m.p. 124-l26C. Recrystallization from acetic acid and water affords substantially pure 4-(2-nitro-lpropenyl)-hydrocinnamic acid as geecn needles, 6.1 g., m.p. l26.5l27.5C.

Elemental analysis for C, H, NO

Calc.: C, 61.27; H, 5.57; N, 5.96;

Found: C, 61.62; H, 5.58; N, 6.14.

EXAMPLE l2 [2,3,5-Trimetbyl-4-(2-Nitro-l-Propenyl)phenyl]acetic Acid Step A: 2',3',5'-Trimethyl-4'- Acetamidoacetophenone To a solution of 2,3,6-trimethylacetanilide (17.7 g., 0.1 mole) and acetyl chloride (23.6 g., 0.3 mole) in dichloromethane (100 ml.) cooled in an ice bath is added slowly aluminum chloride (26.6 g., 0.2 mole). After the addition is complete, the reaction mixture is warmed slowly to reflux for two hours. The solvent is decanted and to the residue is added ice water (100 ml.) and concentrated hydrochloric acid ml.). The product is extracted with chloroform. The chloroform extract is washed with water and dried over anhydrous magnesium sulfate. The solution is filtered and the solvent removed at reduced pressure to yield 2',3',5'-trimethyl- 4'-acetamidoacetophenone.

Step B: (2,3,5-Trimethyl-4-Acetamidophenyl )thi oacetomorpholide By substituting for the 3-chloro-4- acetamidoacetophenone of Example 2, Step A, an equivalent amount of 2',3',5'-trimethyl-4'- acetamidoacetophenone and following substantially the procedure described therein, there is obtained (2,3- ,5-trimethyl-4-acetamidophenyl)thioacetomorpholide.

Step C: (2,3,5-Trimethyl-4-Aminophenyl)acetic Acid By substituting for the (3-chloro-4- acetamidophenyl)-thioacetomorpholide of Example 2, Step B, an equivalent amount of (2,3,5-trimethyl-4- acetamidophenyl)thioacetomorpholide and following substantially the procedure described therein, there is obtained (2,3,5-trimethyl-4-aminophenyl)acetic acid.

Step D: (2,3,5-Trimethyl-4-Cyanophenyl)acetic acid By substituting for the (3-chloro-4-aminophenyl)acetic acid of Example 2, Step C, an equimolar quantity of (2,3,5-trimethyl-4-aminophenyl)acetic acid and following substantially the procedure described therein, there is obtained (2,3,5-trimethyl-4-eyanophenyl)acetic acid.

Step E:

Acid

By substituting for the (3-chloro-4-cyanophenyl)acetic acid of Example 2, Step D, an equimolar quantity of (2,3,5-trimethyl-4-cyanophenyl)acetic acid and following substantially the procedure described therein, there is obtained (2,3,5-trimethyl-4-formylphenyl)acetic acid.

Step F: [2,3,5-Trimethyl-4-(2-Nitro-l-Propenyl)- phenyl]acetic acid By substituting for the (3-chloro-4-formylphenyl)acetic acid of Example 2, Step E, an equimolar quantity of (2,3,5-trimethyl-4-formylphenyl)acetic acid and following substantially the procedure described therein, there is obtained [2,3,5-trimethyl-4-(2-nitro-lpropenyl)phenyl]acetic acid.

(2,3 ,5-Trimethyl-4-Formylphenyl )acetic EXAMPLE 13 [2,3 ,5 ,6-Tetramethyl-4-( 2-Nitrol -Propenyl)phenyl]acetic Acid Step A: 2',3 ,5 ,6'-Tetramethyl-4- Acetamidoacetophenone To a solution of 2,3,5,6-Tetramethylacetanilide (19.13 g., 0.1 mole) and acetyl chloride (23.6 g., 0.3 mole) in dichloromethane (100 ml.) cooled in an ice bath is added slowly aluminum chloride (26.6 g., 0.2 mole). After the addition is complete, the reaction mixture is warmed slowly to reflux for 2 hours. The solvent is decanted and to the residue is added ice water l()() ml.) and concentrated hydrochloric acid (1() ml). The reaction mixture is worked up substantially as in Example 12, Step A, to obtain 2,3,5,6'-tetramethyl-4- acetamidoacetophenone.

Step B: (2,3,5,6-Tetramethyl-4-Acetamidophenyl)- thioacetomorpholide By substituting for the 3-chloro-4- acetamidoacetophenone of Example 2, Step A, an equivalent amount of 2',3'5,6-tetramethyl-4'- acetamidoacetophenone and following substantially the procedure described therein, there is obtained (2,3- ,5,6-tetramethyl-4-acetamidophenyl)thioacetomorpholide.

Step C: (2,3,5,6-Tetramethyl-4-Aminophenyl)acetic Acid By substituting for the (3-chloro-4- acetamidophenyl)-thioacetomorpholide of Example 2, Step B, and equivalent amount of (2,3,5,6-tetramethyl- 4-acetamidophenyl)thioacetomorpholide and following substantially the procedure described therein. there is obtained (2,3,5,6-tetramethyl-4-aminophcnyl )acetic acid.

Step D: (2,3,5,6-Tetramethyl-4-Cyanophenyl)acetic Acid By substituting for the (3-chloro-4-aminophenyl)acetic acid of Example 2, Step C, an equimolar quantity of (2,3,5,6-tetramethyl-4-aminophenyl)acetic acid and following substantially the procedure described therein, there is obtained (2,3,5,6-tctramethyl-4- cyanophenyl)acetic acid Step E: (2,3,5,6-Tetramethyl-4-Formylphenyl)acetic Acid By substituting for the (3-chloro-4-cyanophcnyl)acetic acid of Example 2, Step D, an equimolar quantity of (2,3,5,6-tetramethyl-4-cyanophenyl)acetic acid and following substantially the procedure described therein, there is obtained (2,3,5,6-tetramcthyl-4- formylphenyl)acetic acid.

Step F: [2,3,5,6-Tetramethyl-4-( 2-Nitrol- Propenyl)-phenyl]acetic Acid By substituting for the (3-chloro-4-formylphenyl)acetic acid of Example 2, Step E, an equimolar quantity of (2,3,5,6-tetramethyl-4-formylphenyl)acetic acid and following substantially the procedure described therein, there is obtained [2,3,5,6-tetramethyl-4-(2- nitro-l -propenyl)phenyl]acetic acid.

By following the procedure as described in Example 2, Steps A-E, all of the products described in the following table may be prepared. Thus, by substituting the appropriately substituted acetamidoacetophenone for the 3-chloro-4-acetamidoacetophenone of Example 2, Step A, and by following the procedure of Example 2, Steps A-D, there is produced the corresponding substituted formylphenylacetic acid. Then by substituting the formylphenylacetic acid and an appropriate amine for the n-butylamine, there is produced the corresponding [(N-substituted formimidoyl)phenyllacetic acid. Then by substituting the [(N-substituted formimidoyl)- phenyl]-acetic acid and an appropriate nitroalkane or substituted nitroalkane for the l4-(N-nbutylformimidoyl)-3-chlorophenyl]-acetic acid and nitroethane of Example 2, Step E, and by following substantially the procedure described therein, all the products described in Table I may be prepared. The following equation illustrates the reactions of Example 2, Steps A-E, and, together with Table 1, illustrate the starting materials, intermediates and [(2-nitro-lalkenyl)-phenyl]acetic acid products obtained:

LE 9ntim R R ,x y"

22 -CH Br (CH2) 011 H H 23 CF3 (CH2) on CH3 CH3 24 CH2OH (CH2) on c1 a 25 CN H 26 CH2 (CH2) '3CH3 c1 n CH2CH2 27 -CH2CH2 (CH2) on c1 H The novel compounds of this invention are diuretic and saluretic agents which can be administered in a wide variety of therapeutic dosages in conventional vehicles as, for example, by oral administration in the form of a tablet or by intravenous injection. Also, the daily dosage of the products may be varied over a wide range varying from 5 to 500 mg. The product is preferably administered in subdivided doses in the form of scored tablets containing 5, 10, 25, 50, 100, 150, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. These dosagea are well below the toxic or lethal dose of the products.

A suitable unit dosage form of the products of this invention can be administered by mixing 50 milligrams of a [(2-nitro-l-alkenyl)aryl]alkanoic (and alkenoic)acid (I) or a suitable salt, ester or amide derivative thereof, with 149 mg. of lactose and 1 mg. of magnesium stearate and placing the 200 mg. mixture into a No. l gelatin capsule. Similarly, by employing more of the active ingredient and less lactose, other dosage forms can be put up in No. 1 gelatin capsules and, should it be necessary to mix more than 200 mg. of ingredients together, larger capsules may be employed. Compressed tablets, pills, or other desired unit dosages can be prepared to incorporate the compounds of this invention by conventional methods and, if desired, can be made up as elixirs or as injectable solutions by methods well known to pharmacists.

It is also within the scope of this invention to combine two or more of the compounds of this invention in a unit dosage form or to combine one or more of the compounds of this invention with other known diuretics and saluretics or with other desired therapeutic and- /or nutritive agents in dosage unit form.

The following example is included to illustrate the preparation of a representative dosage form:

EXAMPLE 28 Dry-filled capsules containing 50 mg. of active ingredient per capsule Pergapsule [3-Chloro-4-(2-Nitro-l- PropenyUphenyllacetic Acid mg. Lactose 14) mg. Magnesium Stearate l mg. Capsule (Size No 1) 200 mg.

The [3-chloro-4-(2-nitro-l-propenyl)phenyllacetic acid is reduced to a No. powder and then lactose and magnesium stearate are passed through a No. 60 bolting cloth onto the powder and the combined ingredients admixed for l0 minutes and then filled into a No. 1 dry gelatin capsule.

Similar dry-filled capsules can be prepared by replac ing the active ingredient of the above example by any of the other novel compounds of this invention.

It will be apparent from the foregoing description that the [(2-nitro-l-alkenyl)aryl]alkanoic (and alkenoic)acid products (I) of this invention constitute a valuable class of compounds which have not been prepared heretofore. One skilled in the art will also appreciate that the processes disclosed in the above examples are merely illustrative and are capable of a wide variation and modification without departing from the spirit of this invention.

What is claimed is:

l. A compound of the formula:

(X) n r wherein R is lower alkyl, lower alkoxy lower alkyl, halo lower alkyl, trihalo lower alkyl, hydroxy lower alkyl, eyano, benzyl or lower cycloalkyl; X is hydrogen, halo or lower alkyl or, taken together, two X radicals on the 5 and 6 carbon atoms of the benzene ring may be joined to form the 1,3-butadienylene linkage; Y is methylene, ethylene, vinylene or methyl substituted vinylene and n is an integer having a value of l-4, or a non-toxic, pharmaceutically acceptable salt or a lower alkyl ester thereof.

2. A compound of the formula:

1 '2 N X 3* o wherein R is lower alkyl and X and X are hydrogen, lower alkyl or halo or X and X taken together, may 

2. A compound of the formula:
 3. A compound according to claim 2 wherein R1 is methyl, X1 is chloro and X2 is hydrogen.
 4. A compound according to claim 2 wherein R1 is methyl and X1 and X2 are joined together to form a 1,3-butadienylene linkage.
 5. A compound according to claim 2 wherein R1 is methyl and X1 and X2 and hydrogen. 